2.1 BONE MARROW TRANSPLANTATION AND AIDS TREATMENT
Although combination antiretroviral therapy can dramatically suppress HIV replication for an extended period in some patients (Carpenter et al., 1996, JAMA 276:146), it alone does not restore immune function (Kelleher et al., 1996, JID 173:321). Several approaches to achieve immune reconstitution have been attempted, including allogeneic bone marrow transplantation and adoptive transfer of lymphocytes (Holland et al., 1989, Ann. Int. Med. 111:973; Lane et al., 1990, Ann. Int. Med. 113:512; Koenig et al., 1995, Nature Med. 1:330; Riddell et al., 1996, Nature Med. 2:216). However, these approaches have not been satisfactory because the transplanted cells are still susceptible to HIV infection. Therefore, cell-based therapy may require the development or isolation of HIV-1 resistant immune cells.
The search for an appropriate animal model for studying HIV infection has led to the recognition that most non-human primate species, including baboons, are naturally resistant to infection by HIV-1 (Morrow et al., 1989, AIDS Res. and Human Retro. 86:233; Allen et al., 1995, J Acq Imm Deficien. Synd. Human Retro. 9:429). Although baboon peripheral blood lymphoid cells are susceptible to non-productive infection with HIV-1 in vitro, repeated inoculations of HIV-1 in vivo failed to result in signs or symptoms of infection during more than three years of observation (McClure et al., 1987, Nature 330:487; Morrow et al. 1989). This suggested that the hematopoietic cells from a baboon donor may remain resistant to HIV-1 infection in a xenogeneic transplant environment, thereby potentially achieving immune reconstitution in an HIV-infected patient.
2.2 PREPARATIVE CONDITIONING REGIMENS FOR BONE MARRPW TRANSPLANTATION
The field of bone marrow transplantation was developed originally to treat bone marrow-derived cancers. It is believed by many that lethal conditioning of a human recipient is required to achieve successful engraftment of donor bone marrow cells in the recipient. Current conventional bone marrow transplantation has still primarily relied upon lethal conditioning approaches to achieve donor bone marrow engraftment. The requirement for lethal irradiation of the host which renders it totally immunocompetent poses a significant limitation to the potential clinical application of bone marrow transplantation to a variety of disease conditions, including solid organ or cellular transplantation, sickle cell anemia, thalassemia and aplastic anemia.
The risk inherent in tolerance-inducing conditioning approaches must be low when less toxic means of treating rejection are available or in cases of morbid, but relatively benign conditions. In addition to solid organ transplantation, hematologic disorders, including aplastic anemia, severe combined immunodeficiency (SCID) states, thalassemia, diabetes and other autoimmune disease states, sickle cell anemia, and some enzyme deficiency states, may all significantly benefit from a nonlethal preparative regimen which would allow partial engraftment of allogeneic or even xenogeneic bone marrow to create a mixed host/donor chimeric state with preservation of immunocompetence and resistance to GVHD. Moreover, the use of bone marrow from an HIV-resistant species offers a potential therapeutic strategy for the treatment of AIDS if bone marrow from a closely related species such as baboon also engrafts under similar nonlethal conditions, thereby producing new hematopoietic cells such as T cells which are resistant to infection by HIV.
A number of sublethal conditioning approaches in an attempt to achieve engraftment of allogeneic bone marrow stem cells with less aggressive cytoreduction have been reported in rodent models (Mayumi and Good, 1989, J Exp Med 169:213; Slavin et al., 1978, J Exp Med 147(3):700; McCarthy et al., 1985, Transplantation 40(1):12; Sharabi et al., 1990, J Exp Med 172(1):195; Monaco et al., 1966, Ann NY Acad Sci 129:190). However, reliable and stable donor cell engraftment as evidence of multilineage chimerism was not demonstrated, and long-term tolerance has remained a question in many of these models (Sharabi and Sachs, 1989, J. Exp. Med. 169:493; Cobbold et al., 1992, Immunol. Rev. 129:165; Qin et al., 1990, Eur. J. Immunol. 20:2737). Moreover, reproducible engraftment has not been achieved, especially when multimajor and multiminor antigenic disparities existed. More importantly, prior to the present invention, nonlethal or sublethal conditioning methods had not been contemplated as a therapeutic modality for HIV infection.